DESCRIPTION: (Abstract from application) Epidemiological, family, and twin studies suggest that a substantial proportion of the phenotypic variation in longevity and functional ability is genetic. One possible explanation is that polymorphisms of single genes with important effects on a metabolic pathway may contribute to the underlying pathogenesis of a number of chronic conditions and the aging process simultaneously. To explore this hypothesis, as well as other areas in the genetics of aging, we propose to initiate and develop a new genetic network [the Pacific Genetic (PacGen) Network] of experts in genetics, epidemiology, geriatrics, biostatistics and environmental science from the University of Hawaii, Kuakini Medical Center, Queen's Medical Center, Stanford University and the Pacific Health Research Institute. The Network will be based on existing elements of the Honolulu Heart Program (HHP), an epidemiologic study of elderly Japanese Americans and the Family Blood Pressure Program, a multi-center study of the genetics of hypertension. It will plan and carryout comprehensive genetic epidemiologic studies in aging utilizing candidate gene/genetic association analysis designs. In Phase I, we will demonstrate the ability of this network to investigate genetic factors associated with longevity and maintenance of functional ability in a population based sample. Utilizing single nucleotide polymorphisms (SNPs) and existing HHP DNA samples linked with phenotypic data on grip strength and other factors measured over 35 years, we will identify 5 high frequency SNPs in each of 6 mitochondrial and nuclear candidate genes (30 SNPs). Candidate genes will be selected based on biologic knowledge the Family Blood Pressure Program, a multi-center study of the genetics of hypertension. It will plan and carryout comprehensive genetic epidemiologic studies in aging utilizing candidate gene/genetic association analysis designs. In Phase I, we will demonstrate the ability of this network to investigate genetic factors associated with longevity and maintenance of functional ability in a population based sample. Utilizing single nucleotide polymorphisms (SNPs) and existing HHP DNA samples linked with phenotypic data on grip strength and other factors measured over 35 years, we will identify 5 high frequency SNPs in each of 6 mitochondrial and nuclear candidate genes (30 SNPs). Candidate genes will be selected based on biologic knowledge linking them with energy homeostasis and/or the generation/detoxification of oxygen free radicals, especially mitochondrial genetic variation. Genotyping assays will be developed for each of the 30 SNPs and each SNP will be genotyped in the 1,953 elderly individuals examined in 1997-1999. We will also recruit a sample of 100 family members of the HHP cohort (ages 55 and above). In that sample we will pilot test phenotypic measures including performance based measures of physical function for future studies. Utilizing HPP data we will explore innovative analytical approaches such as quantile regression methods for dealing with population rate of change data and survival phenotypes and the genes associated with them. During this first phase the PacGen Network will develop and submit proposals for more comprehensive genetic epidemiologic studies (Phase II).